Activity of avibactam against Enterobacter cloacae producing an extended-spectrum class C β-lactamase enzyme

Sushmita D Lahiri, Robert A Giacobbe, Michele R Johnstone, Richard A Alm
Journal of Antimicrobial Chemotherapy 2014, 69 (11): 2942-6

BACKGROUND: Extended-spectrum AmpC (ESAC) β-lactamase enzymes, which are either chromosomally encoded or plasmid encoded, have minor structural changes that broaden their substrate hydrolysis profile. The derepressed AmpC enzyme found once in Enterobacter cloacae CHE was shown to contain a six residue deletion in the H-10 helix in close proximity to the active site. Avibactam is a non-β-lactam inhibitor of Ambler class A, class C and some class D β-lactamases that is in clinical development with several β-lactam agents. It has been shown to inhibit AmpC enzymes, but its microbiological activity against isolates carrying different ESAC enzymes is less well understood.

METHODS: MICs were determined using the broth microdilution technique. RT-PCR analyses were performed to measure the level of ampC expression and whole genome sequencing was performed to enable sequence-based analyses.

RESULTS: Structural analyses of avibactam bound to a representative AmpC β-lactamase suggested that the H-10 helix deletion would impact the potency of the inhibitor. Under standard conditions, the ceftazidime/avibactam and ceftaroline/avibactam MIC values for E. cloacae CHE were 64 and 4 mg/L, respectively, representing a significant decrease in susceptibility over control E. cloacae isolates. However, use of higher avibactam concentrations restored the susceptibility of E. cloacae CHE in a dose-dependent manner. Comparison with other E. cloacae isolates carrying derepressed AmpC enzymes suggested that this difference in inhibition by avibactam was unrelated to the level of AmpC being produced.

CONCLUSIONS: The E. cloacae CHE ESAC enzyme is inhibited less efficiently by avibactam than other E. cloacae AmpC proteins due to a subtle rearrangement of the binding site. Although the variants are not commonly observed, the different ESAC enzymes may be inhibited to varied extents by avibactam.


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